Substituted 2-pyridones and pyrid-2-thiones compounds

ABSTRACT

For inhibiting HMG-CoA reductase and cholesterol synthesis, the novel 2-pyridones and pyrid-2-thiones of the formula ##STR1## in which A is optionally substituted aryl or heterocyclic, 
     B is optionally substituted alkyl, cycloalkyl or aryl, 
     D and E independently are optionally substituted aryl or heterocyclic, H, nitro, cyano, optionally substituted alkyl, alkenyl or imino, amino, alkoxy or acyl, or forms a ring with B, 
     G is O or S, 
     X is --CH 2  --CH 2  -- or --CH═CH--, and 
     R represents a group of the formula ##STR2## and salts thereof.

This is a division of application Ser. No. 441,806, filed Nov. 27, 1989,now U.S. Pat. No. 5,032,602.

The invention relates to new substituted 2-pyridones andpyrid-2-thiones, intermediates for their preparation, their preparationand their use in medicaments.

It has been disclosed that lactone derivatives isolated from fungalcultures are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme Areductase (HMG-CoA reductase) [mevinolin, EP-A 22,478; U.S. Pat. No.4,231,938]. Moreover, certain indole derivatives and pyrazolederivatives are also inhibitors of HMG-CoA reductase [EP-A 1,114,027;U.S. Pat. No. 4,613,610].

New substituted 2-pyridones and pyrid-2-thiones of the general formula(I) ##STR3## in which A represents a 3- to 7-membered heterocycle whichmay contain up to 4 heteroatoms from the series comprising sulphur,oxygen or nitrogen and which is optionally monosubstituted topentasubstituted by identical or different substituents from the seriescomprising halogen, trifluoromethyl, trifluoromethylthio,trifluoromethoxy, straight-chain or branched alkyl, alkylthio,alkylsulphonyl, alkoxy or alkoxycarbonyl each having up to 8 carbonatoms, aryl, arylthio or arylsulphonyl having 6 to 10 carbon atoms or agroup of the formula --NR¹ R², in which

R¹ and R² are identical or different and

denote hydrogen, aryl or arylsulphonyl having 6 to 10 carbon atoms,straight-chain or branched alkyl or alkylsulphonyl having up to 8 carbonatoms, where the last-mentioned radicals are optionally substituted byaryl having 6 to 10 carbon atoms,

denote a group of the formula --COR³ in which

R³ denotes straight-chain or branched alkyl or alkoxy having up to 8carbon atoms or phenyl, or

R¹ and R², together with the nitrogen atom, for a 5- to 7-membered ringwhich may be substituted by straight-chain or branched alkyl having upto 8 carbon atoms,

represents aryl having 6 to 10 carbon atoms, which is optionallymonosubstituted to pentasubstituted by identical or differentsubstituents from the series comprising straight-chain or branchedalkyl, alkylthio, alkylsulphonyl, alkoxy or alkoxycarbonyl each havingup to 10 carbon atoms, which may in turn be substituted by hydroxyl,alkoxy having up to 6 carbon atoms, phenyl or by a group of the formula--NR¹ R², or by aryl, aryloxy, arylthio or arylsulphonyl having 6 to 10carbon atoms, of by halogen, nitro, cyano, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, benzyloxy or a group of theformula --NR¹ R², in which

R¹ and R² have the above mentioned meanings,

B represents cycloalkyl having 3 to 8 carbon atoms,

represents straight-chain or branched alkyl having up to 12 carbonatoms, which is optionally substituted by halogen, cyano, azido,trifluoromethyl, trifluoromethoxy, trifluoromethylthio,trifluoromethylsulphonyl, alkoxy having up to 10 carbon atoms, aryl,aryloxy or arylthio having 6 to 10 carbon atoms or by a 5- to 7-memberedheterocycle having up to 4 heteroatoms form the series comprisingsulphur, oxygen or nitrogen, where these and the aryl radicals mayoptionally be monosubstituted to trisubstituted by identical ordifferent substituents form the series comprising halogen, cyano,trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl,alkoxy, alkylthio or alkylsulphonyl each having up to 8 carbon atoms, orby a group of the formula --NR¹ R² or --COR³, in which

R¹, R² and R³ have the abovementioned meanings,

represents aryl having 6 to 10 carbon atoms, which is optionallymonosubstituted to trisubstituted by identical or different substituentsform the series comprising halogen, cyano, nitro, trifluoromethyl,straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each havingup to 8 carbon atoms or amino,

D and E are identical or different and have the above-mentioned meaningof A, or

represent hydrogen, nitro or cyano,

represent cycloalkyl having 3 to 8 carbon atoms,

represent straight-chain or branched alkyl or alkenyl each having up to12 carbon atoms or imino which are optionally substituted by halogen,azido, 2,5-dioxo-tetrahydro-pyrryl, aryl having 6 to 10 carbon atoms, bya 5- to 7-membered heterocycle having up to 4 heteroatoms form theseries comprising nitrogen, oxygen or sulphur and the correspondingN-oxides or by a group of the formula --NR¹ R², --OR⁴, --COR⁵ or--S(O)_(n) --R⁶, in which

R¹ and R² have the abovementioned meanings,

R⁴ denotes hydrogen or

denotes straight-chain or branched alkyl having up to 10 carbon atoms,which is optionally substituted by hydroxyl, trialkylsilyl having up to10 carbon atoms in the entire alkyl moiety, halogen or aryl having 6 to10 carbon atoms, which may in turn be substituted by halogen, cyano,nitro, hydroxyl, straight-chain or branched alkyl, alkoxy oralkoxycarbonyl each having up to 8 carbon atoms or amino,

denotes trialkylsilyl having up to 10 carbon atoms in the entire alkylmoiety, tetrahydropyranyl or 2,5-dioxo-tetrahydropyrryl,

denotes cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10carbon atoms, which may in turn be substituted by halogen, cyano, nitroor amino, or

denotes a group of the formula --COR⁷, in which

R⁷ denotes straight-chain or branched alkyl having up to 8 carbon atoms,aryl having 6 to 10 carbon atoms or the --NR¹ R² group,

R⁵ denotes hydrogen or straight-chain or branched alkyl having up to 10carbon atoms, which is optionally substituted by hydroxyl, phenyl,halogen or cyano,

denotes aryl having 6 to 10 carbon atoms or a 5- to 7-memberedheterocycle having up to 4 heteroatoms form the series comprisingsulphur, nitrogen or oxygen, which may in turn be substituted byhalogen, amino, hydroxyl, nitro or cyano, or

denotes a group of the formula --NR¹ R² or --OR⁴,

n denotes a number 0, 1 or 2,

R⁶ denotes straight-chain or branched alkyl having up to 10 carbonatoms, which may be substituted by halogen, hydroxyl, phenyl or a groupof the formula --NR¹ R²,

denotes aryl having 6 to 10 carbon atoms, which may be substituted byhalogen, hydroxyl, cyano, nitro or amino, or

denotes a group of the formula --NR¹ R² if n represents the number 2,

or

D and E are identical or different and

represent a group of the formula --NR¹ R², --OR⁴ or --COR⁵, in which

R¹, R², R⁴ and R⁵ have the abovementioned meanings,

or

D or E, together with B, form a 5- to 7-membered saturated orunsaturated ring which is optionally substituted by straight-chain orbranched alkyl having up to 8 carbon atoms or phenyl,

G represents an oxygen or sulphur atom,

X represents a group of the formula --CH₂ --CH₂ -- or --CH═CH--, and

R represents a group of the formula ##STR4## in which R⁸ denoteshydrogen or straight-chain or branched alkyl having up to 10 carbonatoms and

R⁹ denotes hydrogen or straight-chain or branched alkyl having up to 10carbon atoms, which may be substituted by phenyl, or

denotes aryl having 6 to 10 carbon atoms or a cation,

or

D represents the --X--R group, in which

X and R have the abovementioned meanings, and their salts have now beenfound.

If R⁹ forms an ester radical with the carboxyl group, a physiologicallytolerable ester radical which is easily hydrolyzed in vivo to give afree carboxyl group and a corresponding physiologically tolerablealcohol is preferably meant by this. These include, for example, alkylesters (C₁ to C₆) and aralkyl esters (C₇ to C₁₀), preferably (C₁-C₄)-alkyl esters and benzyl esters. Moreover, the following esterradicals may be mentioned: methyl esters, ethyl esters, propyl estersand benzyl esters.

If R⁹ represents a cation, a physiologically tolerable metal catio ormamonium cation is preferably meant. Alkali metal cations or alkalineearth metal cations are preferred in this connection, such as, forexample, sodium, potassium, magnesium or calcium cations, and aluminumor ammonium cations, and also non-toxic substituted ammonium cations ofamines such as (C₁ -C₄)-dialkylamines, (C₁ -C₄)-trialkylamines,procaine, dibenzylamine, N,N'-dibenzylethylenediamine,N-benzyl-β-phenylethylamine, N-methylmorpholine or N-ethylmorpholine,1-ephenamine, dihydroabietylamine,N,N'-bis-dihydroabietylethylenediamine, N-lower alkylpiperidine andother amines which can be used for the formation of salts.

Surprisingly, the substituted 2-pyridones and pyrid-2-thiones accordingto the invention show a superior inhibitory action on HMG-CoA reductase(3-hydroxy-3-methyl-glutaryl-coenzyme A reductase).

In the context of the general formula (I) compounds of the generalformula (Ia) and (b) ##STR5## in which A, B, D, E, G, X and R have theabovementioned meanings, are preferred.

Preferred compounds are those of the general formulae (Ia) and (Ib) inwhich

A represents oxiranyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl,indolyl, quinolyl, isoquinolyl, benzothiazolyl or benzimidazolyl, eachof which is optionally monosubstituted to tetrasubstituted by identicalor different substituents form the series comprising fluorine, chlorine,bromine trifluoromethyl, trifluoromethylthio, trifluoromethoxy,straight-chain or branched alkyl, alkylthio, alkylsulphonyl, alkoxy oralkoxycarbonyl each having up to 6 carbon atoms, phenyl, phenylthio,phenylsulphonyl or by a group of the formula --NR¹ R², in which

R¹ and R² are identical or different and

denote hydrogen, phenyl, phenylsulphonyl, straight-chain or branchedalkyl or alkylsulphonyl having up to 6 carbon atoms, benzyl orbenzylsulphonyl, or

denote a group of the formula --COR³, in which

R³ denotes straight-chain or branched alkyl or alkoxy having up to 6carbon atoms or phenyl, or

R¹ and R², together with the nitrogen atom, form a 5- to 7-membered ringwhich may be substituted by straight-chain or branched alkyl having upto 6 carbon atoms,

represents phenyl or naphthyl, each of which is optionallymonosubstituted to tetrasubstituted by identical or differentsubstituents from the series comprising straight-chain or branchedalkyl, alkylthio, alkylsulphonyl, alkoxy or alkoxycarbonyl each havingup to 8 carbon atoms, which may in turn be substituted by hydroxyl,alkoxy having up to 4 carbon atoms, phenyl or by a group of the formula--NR¹ R², or by phenyl, phenyloxy, phenylthio, phenylsulphonyl,fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, benzyloxy or by a group of theformula --NR¹ R²,

B represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

represents straight-chain or branched alkyl having up to 10 carbonatoms, which is optionally substituted by fluorine, chlorine, bromine,cyano, azido, trifluoromethyl, trifluoromethoxy, trifluoromethylthio,trifluoromethylsulphonyl, alkoxy having up to 8 carbon atoms or byphenyl, phenyloxy, or phenylthio, thienyl, furyl, pyridyl, pyrimidyl orquinolyl which may in turn be monosubstituted or disubstituted byidentical or different substitutions from the series comprisingfluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy,straight-chain or branched alkyl, alkoxy, alkylthio or alkylsulphonyleach hiving up to 6 carbon atoms, or by a group of the formula --NR¹ R²or --COR³,

represents phenyl which is optionally monosubstituted or disubstitutedby identical or different substituents from the series comprisingfluorine, chlorine, bromine, cyano, nitro, trifluoromethyl,straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each havingup to 6 carbon atoms or amino,

D and E are identical or different and have the above-mentioned meaningof A and are identical or different to this, or

represent hydrogen, nitro or cyano,

represent cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

represent straight-chain or branched alkyl or alkenyl each having up to10 carbon atoms or imino which are optionally substituted by fluorine,chlorine, bromine, azido, 2,5-dioxo-tetrahydropyrryl, phenyl, pyrimidyl,pyrryl, pyrrolidinyl, morpholino or morpholino-N-oxide, or by a group ofthe formula NR¹ R², --OR⁴, --COR⁵ or --S(O)_(n) --R⁶, in which

R¹ and R² have the abovementioned meanings,

R⁴ denotes hydrogen or

denoted straight-chain or branched alkyl having up to 8 carbon atoms,which is optionally substituted by hydroxyl, trialkylsilyl having up to8 carbon atoms in the entire alkyl moiety, fluorine, chlorine, bromineor by phenyl which may in turn be substituted by fluorine, chlorine,bromine, cyano, nitro, hydroxyl, straight-chain or branched alkyl,alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or amino,

denotes trialkylsilyl having up to 8 carbon atoms in the entire alkylmoiety, tetrahydropyranyl or 2,5-dioxo-tetrahydropyrryl,

denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl whichmay in turn be substituted by fluorine, chlorine, bromine, cyano, nitroor amino, or

denotes a group of the formula --COR⁷, in which

R⁷ denotes straight or branched alkyl having up to 6 carbon atoms, whichis optionally substituted by hydroxyl, phenyl, fluorine, chlorine,bromine or cyano,

denotes phenyl, naphthyl, pyrryl, pyrimidyl, pyridyl, pyrrolidinyl ormorpholino which may in turn be substituted by fluorine, chlorine,bromine, amino, hydroxyl, nitro or cyano, or

denotes a group of the formula --NR¹ R² or --OR⁴,

n denotes a number 0 or 2,

R⁶ denotes straight-chain or branched alkyl having up to 8 carbon atoms,which may be substituted by fluorine, chlorine, bromine, hydroxyl,phenyl or by a group of the formula --NR¹ R²,

denotes phenyl which may be substituted by fluorine, chlorine, bromine,hydroxyl, cyano, nitro or amino, or

denotes a group of the formula --NR¹ R² if n represents the number 2,

or

D and E are identical or different and

represent a group of the formula --NR¹ R², --OR⁴ or --COR⁵, in which

R¹, R², R⁴ and R⁵ have the abovementioned meanings,

or

D or E, together with B, form a 5- to 7-membered saturated orunsaturated ring which is optionally substituted by straight-chain orbranched alkyl having up to 8 carbon atoms or phenyl,

G represents an oxygen or sulphur atom,

X represents a group of the formula --CH₂ --CH₂ -- or --CH═CH--, and

R represents a group of the formula ##STR6## in which R⁸ denoteshydrogen or straight-chain or branched alkyl having up to 8 carbon atomsand

R⁹ denotes hydrogen or straight-chain or branched alkyl having up to 8carbon atoms or benzyl, or

denotes phenyl or a cation,

or

D represents the group of the formula --X--R, in which

X and R have the abovementioned meanings, and their salts.

Particularly preferred compounds of the general formulae (Ia) and (Ib)are those in which

A represents oxiranyl, pyridyl, pyrimidyl, quinolyl or isoquinolyl, eachof which is optionally monosubstituted to trisubstituted by identical ordifferent substituents form the series comprising fluorine, chlorine,trifluoromethyl, straight-chain or branched alkyl, alkylthio,alkylsulphonyl, alkoxy or alkoxycarbonyl each having up to 4 carbonatoms, phenyl, phenylthio, phenylsulphonyl or by a group of the formula--NR¹ R², in which

R¹ and R² are identical or different and

denote hydrogen, phenyl, phenylsulphonyl, straight-chain or branchedalkyl or alkylsulphonyl having up to 4 carbon atoms, benzyl orbenzylsulphonyl,

denote a group of the formula --COR³, in which

R³ denotes straight-chain or branched alkyl or alkoxy having up to 4carbon atoms or phenyl,

or

R¹ and R², together with the nitrogen atom, form a 5- to 7-membered ringwhich may be substituted by straight-chain or branched alkyl having upto 4 carbon atoms,

represents phenyl which is optionally monosubstituted to trisubstitutedby identical or different substituents from the series comprisingstraight-chain or branched alkyl, alkylthio, alkylsulphonyl, alkoxy oralkoxycarbonyl each having up to 6 carbon atoms, which may in turn besubstituted by hydroxyl, methoxy, ethoxy, propoxy, phenyl or by a groupof the formula --NR¹ R², or by phenyl, phenyloxy, fluorine, chlorine,nitro, cyano, trifluoromethyl, benzyloxy or a group of the formula --NR¹R², in which

R¹ and R² have the abovementioned meanings,

B represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

represents straight-chain or branched alkyl having up to 10 carbonatoms, which is optionally substituted by fluorine, chlorine, cyano,azido, alkoxy having up to 6 carbon atoms, phenyl or phenoxy which arein turn substituted by fluorine, chlorine, cyano, straight-chain orbranched alkyl or alkoxy having up to 4 carbon atoms or by a group ofthe formula --NR¹ R² or --COR³,

represents phenyl which is substituted by fluorine, chlorine, nitro,straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each havingup to 4 carbon atoms or amino,

D and E are identical or different and have the above-mentioned meaningof A and are identical or different to this, or

represent hydrogen, nitro or cyano,

represent cyclopropyl, cyclopentyl or cyclohexyl,

represent straight-chain or branched alkyl or alkenyl each having up to8 carbon atoms or imino which are optionally substituted by fluorine,chlorine, azido, 2,5-dioxo-tetrahydropyrryl, phenyl, pyrrolidinyl,morpholino or morpholino-N-oxide, or are substituted by a group of theformula NR¹ R², --OR⁴, --COR⁵ or --S(O)_(n) --R⁶, in which

R¹ and R² have the abovementioned meanings,

R⁴ denotes hydrogen or

denotes straight-chain or branched alkyl having up to 6 carbon atoms,which is optionally substituted by hydroxyl, dimethyl-tert.-butylsilyl,fluorine, chlorine or by phenyl which may in turn be substituted byfluorine, chlorine, hydroxyl or amino,

denotes trialkylsilyl having up to 6 carbon atoms in the entirealkylmoiety, tetrahydropyranyl or 2,5-dioxo-tetrahydropyrryl,

denotes cyclopropyl, cyclopentyl, cyclohexyl or phenyl, or

denotes a group of the formula --COR⁷, in which

R⁷ denotes straight-chain or branched alkyl having up to 4 carbon atoms,phenyl or a group of the formula --NR¹ R²,

R⁵ denotes hydrogen, straight-chain or branched alkyl having up to 6carbon atoms, which is optionally substituted by hydroxyl, phenyl,fluorine or chlorine,

denotes phenyl, pyrryl, pyrrolidinyl or morpholino, or

denotes a group of the formula --NR¹ R² or --OR⁴,

n denotes a number 0 or 2,

R⁶ denotes straight-chain or branched alkyl having up to 6 carbon atoms,which may be substituted by fluorine, chlorine, hydroxyl, phenyl or by agroup of the formula --NR¹ R²,

denotes phenyl which may be substituted by fluorine, chlorine, hydroxyl,cyano, nitro or amino,

denotes a group of the formula --NR¹ R² if n represents the number 2,

or

D and E are identical or different and

represent a group of the formula --NR¹ R², --OR⁴ or --COR⁵, in which

R¹, R², R⁴ and R⁵ have the abovementioned meanings,

or

D or E, together with B, form a 5- to 7-membered saturated orunsaturated ring which is optionally substituted by methyl, ethyl,propyl, isopropyl, butyl, tert.butyl or phenyl,

G represents an oxygen or sulphur atom,

X represents a --CH═CH-- group and

R represents a group of the formula ##STR7## in which R⁸ denoteshydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ortert.butyl, and

R⁹ denotes hydrogen, methyl, ethyl, propyl. isopropyl, butyl, isobutyl,tert.butyl or benzyl, or

denotes a sodium, potassium, calcium, magnesium or ammonium ion

or

D represents the group of the formula --X--R, in which

X and R have the abovementioned meanings, and their salts.

The substituted 2-pyridones and pyrid-2-thiones of the general formula(I) according to the invention have several asymmetric carbon atoms andcan therefore exist in various stereochemical forms. The inventionrelates to both the individual isomers and their mixtures.

Depending on the meaning of the group X and the radical R, differentstereoisomers result which are intended to be explained in more detailin the following:

(a) If the group --X-- represents a group of the formula --CH═CH--, thecompounds according to the invention can exist in two stereoisomericforms which may have the E configuration (II) or the Z configuration(III) of the double bond: ##STR8## (A, B, D, E, G and R have theabovementioned meanings).

Preferred compounds are those of the general formula (I) which have theE configuration (II).

(b) If the radical --R-- represents a group of the formula ##STR9## thecompounds of the general formula (I) have at least two asymmetric carbonatoms, namely the two carbon atoms to which the hydroxyl groups arebonded. Depending on the relative position of these hydroxyl groups toeach other, the compounds according to the invention can exist in theerythro configuration (IV) or in the threo configuration (V). ##STR10##of the compounds in the erythro and in the threo configuration, namelythe 3R,5S isomer or 3S,5R isomer (erythro form) and the 3R,5R isomer and3S,5S isomer (threo form).

The isomers which have the erythro configuration are preferred in thiscase, particularly preferably the 3R,5S isomer and the 3R,5S-3S,5Rracemate.

(c) If the radical --R-- represents a group of the formula ##STR11## thesubstituted 2-pyridones and pyrid-2-thiones have at least two asymmetriccarbon atoms, namely the carbon atom to which the hydroxyl group isbonded and the carbon atom to which the radical of the formula ##STR12##is bonded. Depending on the position of the hydroxyl group to the freevalency on the lactone ring, the substituted 2-pyridones andpyrid-2-thiones can be present as cis-lactones (VI) or as trans-lactones(VII). ##STR13##

In turn, both the cis-lactone and the translactone exist as two isomers,namely the 4R,6R isomer and the 4S,6S isomer (cis-lactone), and the4R,6S isomer or 4S,6R isomer (trans-lactone). Preferred isomers are thetrans-lactones. The 4R,6S isomer (trans) and the 4R,6S-4S,6R racemateare particularly preferred in this connection.

For example, the following isomeric forms of the substituted 2-pyridonesand pyrid-2-thiones may be mentioned: ##STR14##

In addition, a process for the preparation f the substituted 2-pyridonesand pyrid-2-thiones of the general formula (I) ##STR15## in which A, B,D, E, G, X and R have the abovementioned meanings, has been found, whichis characterized in that ketones of the general formula (VIII) ##STR16##in which A, B, D, E and G have the abovementioned meanings, and

R¹⁰ represents alkyl, are reduced,

in the case of the preparation of the acids the esters are hydrolyzed,

in the case of the preparation of the lactones the carboxylic acids arecyclized,

in the case of the preparation of the salts either the esters or thelactones are hydrolyzed,

in the case of the preparation of the ethylene compounds (X═--CH₂ --CH₂--) the ethene compounds (X═--CH═CH--) are hydrogenated by customarymethods, and, if appropriate, isomers are separated.

The process according to the invention can be illustrated by thefollowing equation: ##STR17##

Reduction can be carried out using the customary reducing agents,preferably using those which are suitable for the reduction of ketonesto hydroxy compounds. Reduction using metal hydrides or complex metalhydrides in inert solvents, if appropriate in the presence of atrialkylborane, is particularly suitable in this connection. Reductionis preferably carried out using complex metal hydrides such as, forexample, lithium borohydride, sodium borohydride, potassium borohydride,zinc borohydride, lithium trialkylborohydrides, sodiumtrialkylborohydrides, sodium cyanoborohydride or lithium aluminumhydride. Reduction is very particularly preferably carried out usingsodium borohydride in the presence of triethylborane.

Suitable solvents in this connection are the customary organic solventswhich do not change under the reaction conditions. These preferablyinclude ethers such as, for example diethyl ether, dioxane,tetrahydrofuran or dimethoxyethane, or halogenated hydrocarbons such as,for example, dichloromethane, trichloromethane, tetrachloromethane,1,2-dichloroethane, or hydrocarbons such as, for example, benzene,toluene or xylene. It is likewise possible to employ mixtures of thesolvents mentioned.

Reduction of the ketone group to the hydroxyl group is particularlypreferably carried out under conditions in which the other functionalgroups such as, for example, the alkoxycarbonyl group are not changed.The use of sodium borohydride as a reducing agent in the presence oftriethylborane in insert solvents such as, preferably, ethers isparticularly suitable for this purpose.

Reduction is in general carried out in a temperature range from -80° C.to +30° C., preferably form -78° C. to 0° C.

The process according to the invention is in general carried out atatmospheric pressure. However, it is also possible to carry out theprocess at reduced pressure or at elevated pressure (for example in arange from 0.5 to 5 bar).

In general, the reducing agent is employed in an amount from 1 to 2moles, preferably from 1 to 1.5 moles, relative to 1 mole of the ketocompound.

Under the abovementioned reaction conditions, the carbonyl group is ingeneral reduced to the hydroxyl group without reduction of the doublebond to a single bond taking place.

In order to prepare compounds of the general formula (I) in which Xrepresents an ethylene grouping, the reduction of the ketones (VIII) canbe carried out under those conditions under which both the carbonylgroup and the double bond are reduced.

Further, it is also possible to carry out the reduction of the carbonylgroup and the reduction of the double bond in two separate steps.

The carboxylic acids in the context of the general formula (I)correspond to the formula (Ic) ##STR18## in which A, B, D, E, G and R⁸have the abovementioned meanings.

The carboxylic acid esters in the context of the general formula (I)correspond to the formula (Id) ##STR19## in which A, B, D, E, G and R⁸have the abovementioned meanings, and

R¹⁰ represents alkyl.

The salts of the compounds according to the invention in the context ofthe general formula (I) correspond to the formula (Ie) ##STR20## inwhich A, B, D, E, G and R⁸ have the abovementioned meanings, and

M^(n+) represents a cation, where n indicates the valency.

The lactones in the context of the general formula (I) correspond to theformula (If) ##STR21## in which A, B, D, E, G and R⁸ have theabovementioned meanings,

In order to prepare the carboxylic acids of the general formula (Ic)according to the invention, the carboxylic acid esters of the generalformula (Id) or the lactones of the general formula (If) are in generalhydrolyzed by customary methods. Hydrolysis is in general carried out bytreating the esters or the lactones with customary bases in inertsolvents, whereupon the salts of the general formula (Ie) in generalfirst result, which can then be converted by treating with acid in asecond step into the free acids of the general formula (Ic).

Suitable bases for hydrolysis are the customary inorganic bases. Thesepreferably include alkali metal hydroxides or alkaline earth metalhydroxides such as, for example, sodium hydroxide, potassium hydroxideor barium hydroxide, or alkali metal carbonates such as sodium carbonateor potassium carbonate or sodium hydrogen carbonate, or alkali metalalkoxides such as sodium ethoxide, sodium methoxide, potassiummethoxide, potassium ethoxide or potassium tert.butoxide. Sodiumhydroxide or potassium hydroxide are particularly preferably employed.

Suitable solvents for the hydrolysis are water or the organic solventscustomary for hydrolysis. These preferably include alcohols such asmethanol, ethanol, propanol, isopropanol or butanol, or ethers such astetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulphoxide.Alcohols such as methanol, ethanol, propanol or isopropanol areparticularly preferably used. Likewise, it is also possible to employmixtures of the solvents mentioned.

Hydrolysis is in general carried out in a temperature range from 0° C.to +100° C., preferably from +20° C. to +80° C.

In general, hydrolysis is carried out at atmospheric pressure. However,it is also possible to work at reduced pressure or at elevated pressure(for example from 0.5 to 5 bar).

when carrying out the hydrolysis, the base is in general employed in anamount from 1 to 3 moles, preferably from 1 to 1.5 moles, relative to 1mole of the ester or lactone. Molar amounts of reactants areparticularly preferably used.

When carrying out the reaction, the salts of the compounds (Ie)according to the invention are formed in the first step as intermediateswhich can be isolated. The acids (Ic) according to the invention areobtained by treating the salts (Ie) with customary inorganic acids.These preferably include mineral acids such as, for example,hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid.It has proved advantageous in this connection in the preparation of thecarboxylic acids (Ic) to acidify the basic reaction mixture from thehydrolysis in a second step without isolation of the salts. The acidscan then be isolated in a customary manner.

In order to prepare the lactones of the formula (If) according to theinvention, the carboxylic acids (Ic) according to the invention are ingeneral cyclized by customary methods, for example by heating thecorresponding acid in inert organic solvents, if appropriate in thepresence of molecular sleeves.

Suitable solvents in this connection are hydrocarbons such as benzene,toluene, xylene, mineral oil fractions, or tetralin or diglyme ortriglyme. Benzene, toluene or xylene is preferably employed. Likewise,it is possible to employ mixtures of the solvents mentioned.Hydrocarbons, in particular toluene, in the presence of molecular sievesare particularly preferably used.

Cyclization is in general carried out in a temperature range from -40°C. to +200° C., preferably from -25° C. to +50° C.

cyclization is in general carried out at atmospheric pressure, but it isalso possible to carry out the process at reduced pressure or atelevated pressure (for example in a range from 0.5 to 5 bar).

Moreover, the cyclization is also carried out in inert organic solventswith the aid of cyclizing or water-eliminating agents. Carbodiimides arepreferably used as water-eliminating agents in this connection.N,N'-Dicyclohexylcarbodiimide paratoluenesulphonate,N-cyclohexyl-N'-[2-(N''-methylmorpholinium)ethyl]carbodiimide orN-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride arepreferably employed as carbodiimides.

Suitable solvents in this connection are the customary organic solvents.These preferably include ethers such as diethyl ether, tetrahydrofuranor dioxane, or chlorinated hydrocarbons such as methylene chloride,chloroform or carbon tetrachloride, or hydrocarbons such as benzene,toluene, xylene or mineral oil fractions. Chlorinated hydrocarbons suchas, for example methylene chloride, chloroform or carbon tetrachloride,or hydrocarbons such as benzene, toluene, xylene, or mineral oilfractions are particularly preferred. Chlorinated hydrocarbons such as,for example, methylene chloride, chloroform or carbon tetrachloride arevery particularly preferably employed.

The reaction is in general carried out in a temperature range from 0° C.to +80° C., preferably from 10° C. to +50° C.

When carrying out the cyclization, it has proved advantageous to employthe cyclization methods with the aid of carbodiimides as dehydratingagents.

The resolution of the isomers into the stereoisomerically uniformconstituents is in general carried out by customary methods such as, forexample, are described by E. L. Eliel, Stereochemistry of CarbonCompounds, McGraw Hill, 1962. The resolution of the isomers from theracemic ester step is preferred in this connection. Particularlypreferably in this connection, the racemic mixture of the trans-lactone(VII) is converted by treating by customary methods either with D-(+)-or L-(-)-α-methylbenzylamine into the diastereomeric dihydroxyamides(Ig) ##STR22## which can subsequently be separated into the individualdiastereomers as customary by chromatography or crystallization.Following hydrolysis of the pure diastereomeric amides by customarymethods, for example by treating the diastereomeric amides withinorganic bases such as sodium hydroxide or potassium hydroxide in waterand/or organic solvents such as alcohols, for example methanol, ethanol,propanol or isopropanol, the corresponding enantiomerically puredihydroxy acids (Ic) result which can be converted into theenantiomerically pure lactones by cyclization as described above. Ingeneral, it applies to the preparation of the compounds of the generalformula (I) according to the invention in enantiomerically pure formthat the configuration of the final products according to the methodsdescribed above is dependent on the configuration of the startingsubstances.

The resolution of isomers is intended to be illustrated by way ofexample in the following equation: ##STR23##

The ketones (VIII) employed as starting substances are new.

A process for the preparation of the ketones of the general formula(VIII) according to the invention ##STR24## in which A, B, D, E, G andR¹⁰ have the abovementioned meanings,

has been found, which is characterized in that aldehydes of the generalformula (IX) ##STR25## in which A, B, D, E and G have the abovementionedmeanings,

are reacted in inert solvents with acetoacetic esters of the generalformula (X) ##STR26## in which R¹⁰ has the abovementioned meaning,

in the presence of bases.

The process according to the invention can be illustrated, for example,by the following equation: ##STR27##

Suitable bases in this connection are the customary strong basiccompounds. These preferably include organolithium compounds such as, forexample, n-butyllithium, sec.butyllithium, tert.butyllithiumorphenyllithium, or amides such as, for example, lithiumdiisopropylamide, sodium amide or potassium amide, or lithiumhexamethyldisilylamide, or alkali metal hydrides such as sodium hydrideor potassium hydride. Likewise, it is possible to employ mixtures of thebases mentioned. n-Butyllithium or sodium hydride or their mixture areparticularly preferably employed.

In certain cases, additions of metal halides such as, for example,magnesium chloride, zinc chloride or zinc bromide are advantageous.Addition of zinc halides is particularly preferable.

Suitable solvents in this connection are the customary organic solventswhich do not change under the reaction conditions. These preferablyinclude ethers such as diethyl ether, tetrahydrofuran, dioxane ordimethoxyethane, or hydrocarbons such as benzene, toluene, xylene,cyclohexane, hexane or mineral oil fractions. Likewise, it is possibleto employ mixtures of the solvents mentioned. Ethers such as diethylether or tetrahydrofuran are particularly preferably used.

The reaction is in general carried out in a temperature range from -80°C. to +50° C., preferably from -20° C. to room temperature.

The process is in general carried out at atmospheric pressure, but it isalso possible to carry out the process at reduced pressure or atelevated pressure, for example in a range from 0.5 to 5 bar.

When carrying out the process, the acetoacetic ester is in generalemployed in an amount from 1 to 2, preferably from 1 to 1.5,molesrelative to 1 mole of the aldehyde.

The acetoacetic esters of the formula (X) employed as startingsubstances are known or can be prepared by known methods [Beilstein'sHandbuch der organischen Chemie (Beilstein's Handbook of OrganicChemistry) III, 632; 438].

Examples of acetoacetic esters which may be mentioned for the processaccording to the invention are: methyl acetoacetate, ethyl acetoacetate,propyl acetoacetate and isopropyl acetoacetate.

The preparation of the aldehydes of the general formula (IX) employed asstarting substances is intended to be illustrated by way of example inthe following for the 2-pyridones of the type (Ia). ##STR28##

In this connection, according to scheme A, 2-pyridones of the formula(XI) in which R¹¹ represents an alkyl radical having up to 4 carbonatoms are reduced in the first step [1] in inert solvents such asethers, for example diethyl ether, tetrahydrofuran or dioxane,preferably tetrahydrofuran, using metal hydrides as reducing agents, forexample lithium aluminum hydride, sodium cyanoborohydride, sodiumaluminum hydride, diisobutylaluminum hydride or sodiumbis-(2-methoxyeth.oxy) dihydroaluminate, in temperature ranges from -70°C. to +100° C., preferably from -70° C. to room temperature, or fromroom temperature to +70° C. depending on the reducing agent used, tohydroxymethyl compounds (XII). Preferably, the reduction is carried outusing diisobutyl aluminum hydride in tetrahydrofuran in a temperaturerange from -78° C. to room temperature. The hydroxymethyl compounds(XII) are oxidized in a second step [2] by customary methods to thealdehydes (XIII). The oxidation can be carried out, for example, usingpyridinium chlorochromate, if appropriate in the presence of aluminumoxide, in inert solvents such as chlorinated hydrocarbons, preferablymethylene chloride, in a temperature range from 0° C. to 60° C.,preferably at room temperature, or else using trifluoroacetic acid/dimethyl sulphoxide according to the customary methods of Swernoxidation. The aldehydes (XIII) are reacted in a third step [3] withdiethyl 2-(cyclohexylamino)-vinylphosphonate in the presence of sodiumhydride in inert solvents such as ethers, for example diethyl ether,tetrahydrofuran or dioxane, preferably in tetrahydrofuran, in atemperature range from -20° C. to +40° C., preferably from -5° C. toroom temperature to give the aldehydes (IX).

The pyridones of the formula (XI) employed in this connection asstarting substances are new. They are in general obtained according toscheme B by oxidation of 3,4-dihydropyrid-2-ones (XIV). The oxidation ofthe dihydropyridones (XIV) to the pyridones (XI), in which R¹¹ has theabovementioned meaning, can be carried out, for example, using chromicoxide or sodium nitrite in glacial acetic acid in a temperature rangefrom -20° C. to +150° C., using nitric acid in aqueous suspension orusing ceric salts, such as, for example, ammonium ceric nitrate, in asolvent mixture of acetonitrile and water. Preferably, thedihydropyridones are reacted with ammonium ceric nitrate in a mixture ofacetonitrile and water. ##STR29##

The 3,4-dihydropyrid-2-ones of the general formula (XIV) employed hereas starting substances are new.

They are generally obtained by reaction of suitably substitutedα,β-unsaturated carboxylic acid esters of the general formula (XV), inwhich A, B, D and R¹¹ have the abovementioned meanings andcorrespondingly substituted β-amino-α,β-unsaturated carboxylic esters ofthe general formula (XVI).

The process can be carried out in substance or in a high-boiling solventsuch as, for example, ethylene glycol either under basic conditionsusing alkali metal alkoxides, such as, for example, sodium ethoxide orpotassium ethoxide at room temperature to +200° C., or in glacial aceticacid at room temperature. Reaction with alkali metal alkoxides at +140°C. is preferred.

The reaction can be illustrated by the following equation: ##STR30##

The compounds of the general formula (I), in which A, B, D, E, X and Rhave the abovementioned meanings and G represents sulphur, can beobtained from the 2-pyridones of the general formula (XI), in which A,B, D and E have the abovementioned meanings if appropriate by methodsknown from the literature [A. Y. Guttsait et al., Khim. Geterotsikl.Soedin 1987, 9, 1233-1237].

The pyridones (XI), which are prepared as described above from thedihydropyridones (XIV) by oxidation, can be reduced to the pyridones(XVIII) by means of suitable reducing agents, such as, for example,lithium aluminum hydride, diisobutyl aluminum hydride or sodiumbis-(2-methoxyethoxy)-dihydroaluminate in inert solvents, such as, forexample, tetrahydrofuran or toluene.

The pyridones (XVIII) can be reacted to give the pyridones (XIX) byknown methods, for example by reaction with an alkyl or benzyl halide inthe presence of a base such as, for example, sodium hydride or, forexample, by reaction with a trialkylsilyl halide or an acid halide inthe presence of a base such as imidazole, pyridine or triethylamine. Thehydroxyl group of the pyridones (XVIII) can be converted into a leavinggroup by known methods, for example by reaction withtrifluoromethanesulphonic anhydride, thionyl chloride ormethanesulphonyl chloride in the presence of a base. The leaving groupcan then be exchanged for nucleophiles by known methods. ##STR31##

The radicals A, B, E, R⁴ and R¹¹ of the formulae (XVII), (XVIII) and(XIX) have the abovementioned meanings.

By reaction of the pyridones (XVIII) or (XVII), the radicals A, B andR¹¹ of which have the abovementioned meanings and E represents hydrogen,with alkyl or benzyl halides in the presence of a base such as, forexample, potassium carbonate, sodium hydride or an acid halide in thepresence of a base such as imidazole, pyridine or triethylamine, theN-alkyl or N-acyl derivatives can be prepared.

The compounds of the general formula (I) according to the invention haveuseful pharmacological properties and can be employed in medicaments. Inparticular, they are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA) reductase and, as a result of this, inhibitors of cholesterolbiosynthesis. They can therefore be used for the treatment ofhyperlipoproteinaemia, lipoproteinaemia or atherosclerosis. The activecompounds according to the invention in addition cause a lowering of thecholesterol content of the blood.

The enzyme activity determination was carried out as modified by G. C.Ness et al., Archives of Biochemistry and Biophysics 197, 493-499(1979). Male Rico rats (body weight 300-400 g) were treated for 11 dayswith altromin powdered feed to which 40 g of cholestyramine/kg of feedwere added. After decapitation, the livers were removed from the animalsand placed on ice. The livers were comminuted and homogenized 3 times ina Potter-Elvejem homogenizer in 3 volumes of 0.1 M sucrose, 0.05 M KCl,0.04 M K_(x) H_(y) phosphate, 0.03 M ethylenediaminetetraacetic acid,0.002 M dithiothreitol (SPE) buffer pH 7.2. They were then centrifugedat 15,000 g for 15 minutes and the sediment was discarded. Thesupernatant was sedimented at 100,000 g for 75 minutes. The pellet wastaken up in.1/4 volumes of SPE buffer, homogenized again and thencentrifuged again for 60 minutes at 100,000 g. The pellet was taken upin the 5-fold amount of its volume of SPE buffer, homogenized and frozenand stored at -78° C. (=enzyme solution).

For testing, the test compounds (or mevinolin as reference substance)were dissolved in dimethylformamide with the addition of 5 vol.-% of 1 NNaOH and, using 10 μl employed in various concentrations in the enzymetest. The test was started after 20 minutes' pre-incubation of thecompounds with the enzyme at 37° C. The test batch was 0.380 ml andcontained 4 μmol of glucose 6-phosphate, 1.1 mg of bovine serum albumin,2.1 μmol of dithiothreitol, 0.35 μmol of NADP, 1 unit of glucose6-phosphate dehydrogenase, 35 μmol of K_(x) H_(y) phosphate pH 7.2, 20μl of enzyme preparation and 56 nmol of 3-hydroxy-3-methyl-glutarylcoenzyme A (glutaryl-3-¹⁴ C) 100,000 dpm.

After incubation for 60 minutes at 37° C., the batch was centrifuged and600 μl of the supernatant was applied to a 0.7 × 4 cm column packed witha 5-chloride anion exchanger (100 to 200 mesh). The column was washedwith 2 ml of dist. water and 3 ml of Aquasol were added to runnings pluswashing water and counted in an LKB scintillation counter. IC₅₀ valueswere determined by intrapolation by plotting the percentage inhibitionagainst the concentration of the compound in the test. In order todetermine the relative inhibitory potency, the IC₅₀ value of thereference substance mevinolin was set at 1 and compared with thesimultaneously determined IC₅₀ value of the test compound.

Cholesterol biosynthesis was measured after administration of HMG-CoAreductase inhibitors.

Male rats (about 180 g) receive the test substance in 10 ml/kg of 0.75%strength tragacanth solution 16 h after withdrawal of feed. The controlgroup receives only the vehicle. The animals receive 20 μ Ci of ¹⁴ Cacetate per animal intraperitoneally at various times after substanceadministration. At various times after ¹⁴ C acetate injection, theanimals are sacrificed, the livers are removed and after extraction andsubsequent radioactivity measurement, the cholesterol synthesis rate isdetermined.

The new active compounds can be converted in a known manner into thecustomary formulations, such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, non-toxic, pharmaceutically suitable excipients or solvents. Inthis connection, the therapeutically active compound should in each casebe present in a concentration of about 0.5 to 98% by weight, preferably1 to 90% by weight, of the total mixture, i.e. in amounts which aresufficient in order to achieve the indicated dosage range.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or excipients, optionally using emulsifiersand/or dispersants, where, for example, in the case of the use of wateras a diluent, if appropriate organic solvents can be used as auxiliarysolvents.

Examples of auxiliaries which may be mentioned are: water, non-toxicorganic solvents, such as paraffins (for example mineral oil fractions),vegetable oils (for example groundnut/sesame oil), alcohols (forexample: ethyl alcohol, glycerol), excipients, such as, for example,ground natural minerals (for example kaolins, aluminas, talc, chalk),ground synthetic minerals (for example highly disperse silica,silicates), sugars (for example sucrose, lactose and dextrose),emulsifiers (for example polyoxyethylene fatty acid esters,polyoxyethylene fatty alcohol ethers, alkyl sulphonates and arylsulphonates), dispersants (for example lignin-sulphite waste liquors,methylcellulose, starch and polyvinylpyrrolidone) and lubricants (forexample magnesium stearate, talc, stearic acid and sodium laurylsulphate).

Administration takes place in a customary manner, preferably orally,parenterally, perlingually or intravenously. In the case of oraladministration, tablets may of course also contain additions, such assodium citrate, calcium carbonate and dicalcium phosphate together withvarious additives, such as starch, preferably potato starch, gelatineand the like in addition to the excipients mentioned. Furthermore,lubricants, such as magnesium stearate, sodium lauryl sulphate and talccan additionally be used for tabletting. In the case of aqueoussuspensions, various flavour enhancers or colorants may be added to theactive compounds in addition to the abovementioned auxiliaries.

In the case of parenteral administration, solutions of the activecompound using suitable liquid excipients can be employed.

In general, it has proved advantageous on intravenous administration toadminister amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to0.5 mg/kg of body weight to attain effective results. On oraladministration the dose is about 0.01 to 20 mg/kg, preferably 0.1 to 10mg/kg of body weight.

In spite of this, it may be necessary to deviate from the amountsmentioned, depending on the body weight or the type of administrationroute, on individual behaviour towards the medicament, the manner of itsformulation and the point in time or interval at which administrationtakes place.

Thus, in some cases it may be sufficient to manage with less than thepreviously mentioned minimum amount, whereas in other cases the upperlimit mentioned must be exceeded. In the case of administration ofrelatively large amounts, it may be advisable to divide these intoseveral individual doses over the day.

PREPARATION EXAMPLES EXAMPLE 1 Ethyl 3-amino-4-methyl-pent-2-enoate##STR32##

10.8 g of p-toluenesulphonic acid × 4 H₂ O are added to 500 g (3.16 mol)of ethyl isobutyryl acetate in 1500 ml of toluene p.A., and the mixtureis saturated with ammonia gas at room temperature with stirring andallowed to stand overnight. It is then heated under reflux in a waterseparator and ammonia gas is continuously introduced until thecalculated amount of water has separated (47 ml of water after refluxfor 8 hours). The mixture is allowed to cool overnight, and theprecipitate which deposits is filtered off and washed with toluene. Thecombined toluene phases are washed a number of times with water, driedwith sodium sulphate and concentrated in vacuo, and the residue isdistilled in a high vacuum.

B.p.: 82-85° C. / 1 torr.

Yield: 315 g (63.4% of theory, about 90% pure).

¹ H-NMR (CDCl₃): δ (ppm)=1.13 (d, 6H); 1.25 (t, 3H); 2.32 (sept., 1H);4.12 (q, 2H); 4.56 (s, 1H).

Example 2 Methyl 1-carbomethoxy-2-(4-fluorophenyl)-propenoate ##STR33##

229 ml (2 mol) of dimethyl malonate, 223 ml (2 mol) of4-fluorobenzaldehyde, 40 ml of piperidine and 103 ml of glacial aceticacid are heated under reflux overnight in 1.5 1 of cyclohexane in awater separator. After cooling to room temperature, the mixture is takenup in ethyl acetate, and the solution is washed with water, dried usingsodium sulphate and distilled.

B.p.: 135° C.-140° C. (1 mm).

Yield: 342.9 g (72% of theory).

¹ H-NMR (CDCl₃): δ(ppm)=3.85 (s, 6H); 7.0-7.5 (m, 4H); 7.7 (s, 1H).

Example 3 3-Methyl 5-ethyl3,4-dihydro-4-(4-fluorophenyl)-6-isopropyl-(1H)-pyrid-2-one-3,5-dicarboxylate ##STR34##

114.3 g (0.48 mol) of methyl1-carbomethyoxy-2(4-fluorophenyl)-propenoate, 75.4 g (0.48 mol) of ethyl3-amino-4-methyl-pent-2-enoate, 1 g of sodium methoxide and 5 ml ofethanol were stirred for 60 h at a bath temperature of 140° C. and theproduct was recrystallized from ethanol.

M.p.: 124° C.

Yield: 115.4 g (66% of theory)

H-NMR (CDCl₃): δ (ppm)=1.1-1.3 (m, 9H); 3.55 (d,

1H); 3.75 (s, 3H); 4.1 (q, 2H);

4.2 (sept., 1H); 4.65 (d, 1H);

6.9-7.2 (m, 4H); 7.7 (s, 1H).

Example 4 3-Methyl 5-ethyl4-(4-fluorophenyl)-6-isopropyl-(1H)-pyrid-2-one-3,5-dicarboxylate##STR35##

10.8 g (30 mmol) of the compound from Example 3 and 3.9 g (39 mmol) ofchromium trioxide were heated under reflux in 100 ml of glacial aceticacid, 2 g (20 mmol) of chromium trioxide were added again after 2 h andthe mixture was heated under reflux overnight. The solvent was distilledoff, the residue was dissolved in dilute hydrochloric acid and washedwith ether, and the combined ether phases were washed with water,aqueous sodium hydrogen carbonate solution and water, dried using sodiumsulphate and chromatographed on 70-230 mesh silica gel using ethylacetate/petroleum ether 1:1.

Yield: 5.5 g (51% of theory).

¹ H-NMR (CDCl₃):δ(ppm)=0.9 (tr, 3H); 1.4 (d, 6H); 3.15

(sept., 1H); 3.6 (s, 3H); 3.9

(q, 2H); 7.0 7.3 (m, 4H);

12.2 (s, 1H).

Example 53-Methy15-ethy14-(4-fluorophenyl)-6-isopropyl-1-methyl-pyrid-2-one-3,5-dicarboxylate##STR36##

11.3 g (31 mmol) of the compound from Example 4, 1.2 g (50 mmol) ofsodium hydride and 4 ml (62 mmol) of methyl iodide are heated in 50 mlof dimethylformamide at 80° C. for 2 hours and the mixture is pouredinto 500 ml of water at room temperature and extracted three times using150 ml of ether. The combined organic phases are washed with water anddried using sodium sulphate. After distilling off the solvent in vacuo,11.1 g are obtained.

Crude yield: 95.2% of theory.

¹ H-NMR (CDCl₃):δ(ppm)=0.95 (tr, 3H); 1.3 (d, 6H);

3.15 (sept., 1H); 3.6 (s, 3H);

4.0 (q, 2H); 4.05 (s, 3H); 7.0 -7.3 (m, 4H).

Example 6 Ethyl4-(4-fluorophenyl)-3-hydroxymethyl-6-isopropyl-1-methyl-pyrid-2-one-5-carboxylate##STR37##

1.48 g (3.95 mmol) of the compound from Example 5 are dissolved in 30 mlof toluene, cooled to -78° C. under nitrogen and 6.6 ml (10 mmol) of a1.5 molar solution of diisobutyl aluminum hydride in toluene is addeddropwise at this temperature. The cooling bath is removed and themixture is stirred for 2 hours at room temperature. After hydrolysisusing 20% strength aqueous potassium sodium tartrate solution, theorganic phase is separated off, the aqueous phase is washed three timeswith toluene, and the combined organic phases are washed with saturatedsodium chloride solution and dried using sodium sulphate. Afterdistilling off the solvent in vacuo, 1.52 g of oil are obtained which ischromatographed on silica gel (ethyl acetate/petroleum ether 1:5).

Yield: 520 mg (38% of theory) and 310 mg (21%) of starting material.

¹ H-NMR (CDCl₃):δ(ppm)=0.95 (tr, 3H); 1.3 (d, 6H); 2.3 (tr,1H); 3.1(sept.,1H); 3.95 (q, 2H); 4.05 (s, 3H); 4.4 (d, 2H); 7.0-7.3 (m, 4H).

Example 7 Ethyl4-(4-fluorophenyl)-6-isopropyl-3-methoxymethyl-1-methyl-pyrid-2-one-5-carboxylate##STR38##

10 520 mg (1.5 mmol) of the compound from Example 6 are stirred at roomtemperature for 4 h with 42 mg (1.75 mmol) of sodium hydride and 0.3 ml(4.5 mmol) of methyl iodide in 4 ml of dimethylformamide. The reactionmixture is poured into ice-water, the mixture is washed three times withether, and the combined ether phases are washed with water and saturatedsodium chloride solution and dried using sodium sulphate. After removingthe solvent on a rotary evaporator, 520 mg of oil are obtained.

Yield: 100% of theory.

¹ H-NMR (CDCl₃):δ(ppm)=0.95 (tr, 3H); 1.3 (d, 6H); 3.1 (sept.,1H); 3.25(s, 3H); 3.95 (q, 2H); 4.05 (s, 3H); 4.1 (s, 2H); 7.0-7.3 (m, 4H).

Example 84-(4-Fluorophenyl)-5-hydroxymethyl-6-isopropyl-3-methoxy-methyl-1-methyl-pyrid-2-one##STR39##

1,19 g (3.5 mmol) of the compound from Example 7 were reducedanalogously to Example 6 using 5.2 ml (7.7 mmol) of a 1.5 molar solutionof diisobutylaluminum hydride in toluene. After chromatography on silicagel (ethyl acetate/petroleum ether 1:5), 730 mg of solid are obtained.

Yield: 66% of theory.

¹ H-NMR CDCl₃):δ(ppm)=1.2 (tr, 1H); 1.3 (d, 6H); 3.2 (s, 3H); 3.4(sept., 1H); 4.05 (2s, 5H); 4.35 (d, 2H); 7.1-7.3 (m, 4H).

Example 94-(4-Fluorophenyl)-6-isopropyl-3-methoxymethyl-1-methyl-pyrid-2-one-5-carbaldehyde##STR40##

568 mg (2.64 mmol) of pyridinium chlorochromate are added to a solutionof 0.7 g (2.2 mmol) of the compound from Example 8 in 120 ml ofmethylene chloride, the mixture is stirred overnight at room temperatureand filtered through kieselguhr with suction, the kieselguhr is washedwith 200 ml of methylene chloride, the mixture is filtered throughsilica gel with suction, the silica gel is washed with 200 ml ofmethylene chloride, the filtrate is dried using sodium sulphate and 670mg of oil are obtained after removing the solvent on a rotaryevaporator.

Yield: 96% of theory.

¹ H-NMR CDCl₃):δ(ppm)=1.3 (d, 6H); 3.25 (s, 3H); 4.0 (sept., 1H); 4.08(s, 2H); 4.10 (s, 3H); 7.1-7.3 (m, 4H); 9.7 (s,1H).

Example 10 (E)-3-[4-(4-Fluorophenyl)-6-isopropyl-3-methoxymethyl-1-methyl-pyrid-2-on-5-yl]-prop-2-enal##STR41##

804 mg (3.1 mmol) of diethyl 2-(cyclohexylamino)vinylphosphonatedissolved in 6 ml of dry tetrahydrofuran are added dropwise at -5° C.under nitrogen to a suspension of 59 mg (2.5 mmol) of sodium hydride in6 ml of dry tetrahydrofuran. After 30 minutes, 0.65 g (2.05 mmol) of thecompound from Example 9 in 15 ml of dry tetrahydrofuran are addeddropwise at the same temperature and the mixture is heated to reflux for30 minutes. After cooling to room temperature, the mixture is added to200 ml of ice-cold water and extracted three times using 100 ml each ofethyl acetate. The combined organic phases are washed with saturatedsodium chloride solution and dried over sodium sulphate. Afterconcentrating in vacuo, the residue is taken up in 5 ml of toluene, asolution of 0.9 g (7 mmol) of oxalic acid dihydrate in 12 ml of water isadded and the mixture is heated to reflux for 90 minutes. After coolingto room temperature, the phases are separated, and the organic phase iswashed with saturated sodium chloride solution, dried over sodiumsulphate and concentrated in vacuo. The residue is dissolved inmethylene chloride and filtered through silica gel.

Yield: 560 mg of solid (79.6% of theory).

¹ H-NMR CDCl₃):δ(ppm)=1.3 (d, 6H); 3.25 (s, 3H); 3.35 (sept.,1H); 4.05(s, 5H); 5.9 (dd,1H); 7.05-7.3 (m, 5H); 9.35 (d,1H).

Example 11 Methyl (E)-7-[4-(4-fluorophenyl)-6-isopropyl-3-methoxymethyl-1-methyl-pyrid-2 -on-5-yl]-5-hydroxy-3-oxo-hept-6-enoate ##STR42##

0.35 ml (3.3 mmol) of methyl acetoacetate is added dropwise at -5° C.under nitrogen to a suspension of 80 mg (3.4 mmol) of sodium hydride in3 ml of dry tetrahydrofuran. After 15 minutes, 2.3 ml (3.3 mmol) of 15%strength butyllithium in n-hexane and 3.3 ml (3.3 mmol) of a 1 molarzinc chloride solution in ether are added dropwise at the sametemperature and the mixture is stirred for 15 minutes 530 mg (1.5 mmol)of the compound from Example 10 dissolved in 8 ml of dry tetrahydrofuranare then added dropwise and the mixture is stirred at -5° C. for 30minutes. The reaction solution is cautiously diluted with 100 ml ofsaturated aqueous ammonium chloride solution and the mixture isextracted three times using 100 ml each of ether. The combined organicphases are washed twice with saturated sodium hydrogen carbonatesolution and once with saturated sodium chloride solution, dried oversodium sulphate and concentrated in vacuo.

Crude yield: 760 mg (100% of theory).

¹ H-NMR (CDCl₃):δ(ppm)=1.25 (m, 6H); 2.45 (m, 2H), 3.2 (m, 4H); 3.4 (s,2H); 3.75 (s, 3H); 4.0 (s, 3H); 4.05 (s, 2H); 4.45 (m,1H); 5.2 (dd,1H);6.3 (d,1H); 7.0-7.2 (m, 4H).

Example 12 Methyl erythro-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-3-methoxymethyl-1-methyl-pyrid-2-on-5-]-3,5-dihydroxyhept-6-enoate##STR43##

1.9 ml (1.9 mmol) of 1 M triethylborane solution in tetrahydrofuran areadded at room temperature to a solution of 730 mg (1.6 mmol) of thecompound from Example 11 in 13 ml of dry tetrahydrofuran, air is passedthrough the solution for 5 minutes and the latter is cooled to aninternal temperature of -30° C. 72 mg (1.9 mmol) of sodium borohydrideand, slowly, 1.3 ml of methanol are added, the mixture is stirred at-30° C. for 30 minutes then a mixture of 5 ml of 30% strength hydrogenperoxide and 11 ml of water is added. The temperature is allowed to riseto 0° C. during the course of this and the mixture is stirred for afurther 30 minutes. The mixture is extracted three times using 70 mleach of ethyl acetate, and the combined organic phases are washed onceeach with 10% strength potassium iodide solution, 10% strength sodiumsolution and saturated sodium chloride solution, dried over sodiumsulphate and concentrated in vacuo. The residue is chromatographed on acolumn (100 g of 230-400 mesh silica gel, ethyl acetate/petroleum ether1:2).

Yield: 350 mg of oil (47.6% of theory).

¹ H-NMR CDCl₃):δ(ppm)=1.25 (m, 6H); 1.45 (m, 2H); 2.4 (m, 2H); 3.2 (s,3H); 3.28 (sept.,1H); 3.75 (s, 3H); 4.0 (s, 3H); 4.05 (s, 2H); 4.1 (m,1H); 4.25 (m, 1H); 5.2 (dd, 1H); 6.25 (d,1H); 7.0-7.2 (m, 4H).

Example 13 Ethyl4-(4-fluorophenyl)-3-hydroxymethyl-6-isopropyl-(1H)-pyrid-2-one-5-carboxylate##STR44##

7.02 g (19.45 mmol) of the compound from Example 4 were heated for 2 hunder reflux with 1.17 g (29.2 mmol) of lithium aluminum hydride in 100ml of tetrahydrofuran, the mixture was hydrolyzed using 20% strengthaqueous potassium sodium tartrate solution with ice-cooling and washedwith ether. The combined ether phases are washed with water, dried usingsodium sulphate and purified by chromatography on silica gel (methylenechloride/methanol 20:1) after removing the solvent.

Yield: 1.09 g (16.8% of theory).

¹ H-NMR CDCl₃):δ(ppm)=0.9 (tr, 3H); 1.4 (d, 6H); 3.15 (sept.,1H); 3.9(q, 2H); 4.05 (tr,1H); 4.4 (d, 2H); 7.05-7.3 (m, 4H); 12.4 (s,1H).

Example 14 Ethyl1,6-diisopropyl-4-(4-fluorophenyl)-3-hydroxymethyl-pyrid-2-one-5-carboxylate##STR45##

1.6 g (4.8 mmol) of the compound from Example 13, 1.7 ml (17.3 mmol) of2-iodopropane and 2.3 g of potassium carbonate are heated under refluxfor 5 h in 30 ml of acetone and, after filtering and removing thesolvent, the residue is taken up in methylene chloride, washed withwater, dried using sodium sulphate and chromatographed on silica gel(methylene chloride/methanol 40:1).

Yield:1.14 g (63% of theory).

¹ H-NMR (CDCl₃):δ(ppm)=0.95(tr, 3H); 1.3(d, 6H); 1.45 (d, 6H); 2.5 (tr,1H); 3.1 (sept., 1H); 3.95 (q, 4H); 4.35 (d, 2H); 5.5 (sept., 1H);7.0-7.3 (m, 4H).

Example 15 Ethyl1,6-diisopropyl-4-(4-fluorophenyl)-30-methoxymethyl-pyrid-2-one-5-carboxylate##STR46##

Analogously to Example 7, 1.04 g of oil are obtained starting from 1.1 g(2.93 mmol) of the compound from Example 14, 1.1 ml (17.6 mmol) ofmethyl iodide and 155.mg (6.45 mmol) of sodium hydride.

Crude yield: 91% of theory.

¹ H-NMR (CDCl₃):δ(ppm)=0.95 (tr, 3H); 1.25 (d, 6H); 1.4 (d, 6H); 3.1(sept.,1H); 3.25 (s, 3H); 3.95 (q, 2H); 4.1 (s, 2H); 5.45 (sept.,1H);7.0-7.4 (m, 4H).

Example 161,6-Diisopropyl-4-(4-fluorophenyl)-5-hydroxymethyl-3-methoxymethyl-pyrid-2-one##STR47##

Analogously to Example 8, 680 mg of the title compound are obtainedstarting from 1.02 g (2.57 mmol) of the compound from Example 15.

Yield: 76.2% of theory

¹ H-NMR CDCl₃):δ(ppm)=1.15 (tr,1H); 1.3 (d, 6H); 1.4 (d, 6H); 3.2 (s,3H); 3.4 (sept.,1H); 4.05 (s, 2H); 4.35 (d, 2H); 5.4 (sept.,1H);7.05-7.3 (m, 4H).

Example 171,6-Diisopropyl-4-(4-fluorophenyl)-3-methoxymethyl-pyrid-2-one-3-carbaldehyde##STR48##

Analogously to Example 9, 620 mg of the title compound are obtainedstarting from 680 mg (1.96 mol) of the compound from Example 16.

Yield: 9.16% of theory

¹ H-NMR (CDCl₃):δppm)=1.25 (d, 6H); 1.45 (d, 6H); 3.25 (s, 3H); 4.0(sept., 1H); 4.05 (s, 2H); 5.5 (sept., 1H); 7.1-7.3 (m, 4H); 9.65 (s,1H).

Example 18(E)-3-[1,6-Diisopropyl-4-(4-fluorophenyl)-3-methoxymethyl-pyrid-2-on-5-yl]-prop-2-enal##STR49##

Analogously to Example 10, 550 mg of the title compound are obtainedstarting from 620 mg (1.8 mmol) of the compound from Example 17.

Yield: 82.5% of theory.

¹ H-NMR (CDCl₃):δ(ppm)=1.25 (d, 6H), 1.40 (d, 6H); 3.2 (s, 3H); 3.30 (m,1H); 4.05 (s, 2H); 5.45 (m,1H); 5.85 (dd, 1H); 7.0-7.2 (m, 5H).

Example 19 Methyl(E)-7-[1,6-diisopropyl-4-(4-fluorophenyl)-3-methoxymethyl-pyrid-2-on-5-yl]-5-hydroxy-3-oxo-hept-6-enoate##STR50##

Analogously to Example 11, 1.11 g of crude product are obtained startingfrom 520 mg (1.4 mmol) of the compound from Example 18.

Crude yield: 100% of theory.

¹ H-NMR CDCl₃):δ(ppm)=1.15-1.45 (m, 12H); 2.4 (m, 2H); 3.25 (m, 4H);3.45 (s, 2H); 3.75 (s, 3H); 4.05 (s, 2H); 4.5 (m,1H); 5.2 (dd,1H); 5.4(m,1H); 6.3 (d,1H); 7.0-7.2 (m, 4H).

Example 20 Methyl erythro-(E)-7-[1,6-diisopropyl-4-(4-fluorophenyl)-3-methoxymethyl-pyrid-2-on-5-yl]-3,5-dihydroxy-hept-6-enoate ##STR51##

Analogously to Example 12, 240 mg of oil are obtained starting from 1.05g (2.16 mmol) of the compound of Example 19.

Yield: 22.7% of theory.

¹ H-NMR (CDCl₃):δ(ppm)=1.1-1.5 (m, 14H); 2.40 (m, 2H); 3.25 (m, 4H);3.75 (s, 3H); 4.05 (m, 3H); 4.30 (m, 1H); 5.15 (dd, 1H); 5.40 (m, 1H);6.25 (d,1H); 6.95-7.2 (m, 4H).

Example 213,5-Dihydroxymethyl-4-(4-fluorophenyl)-6-isopropyl-1-methyl-pyrid-2-one##STR52##

Starting from 3.0 g (8 mmol) of the compound of Example 5 and 26.6 ml(40 mmol) of a 1.5 M solution of diisobutyl aluminum hydride in toluene,2.64 g of the title compound are obtained analogously to Example 6.

Crude yield: 100% of theory.

¹ H-NMR (CDCl₃): δ(ppm)=1.20 (tr, 1H); 1.35 (d, 6H); 2.40 (tr, 1H); 3.45(m, 1H); 4.05 (s, 3H); 4.30 (d, 2H); 4,35 (d, 1H); 7.1-7.3 (m, 4H).

Example 224-(4-Fluorophenyl)-6-isopropyl-1-methyl-pyrid-2-one-3,5-dicarbaldehyde##STR53##

Analogously to Example 9, 2.13 g of the title compound are obtainedstarting from 2.60 g (8.5 mmol) of the compound from Example 21.

Yield: 83.3% of theory.

¹ H-NMR CDCl₃):δ(ppm)=1.35 (d, 6H); 4.0 (m,1H); 4.2 (s, 3H); 7.15-7.3(m, 4H); 9.65 (s,1H); 9.95 (s,1H).

Example 23(E,E)-3,3-[4-(4-Fluorophenyl)-6-isopropyl-1-methyl-pyrid-2-one-3,5-diyl]-diprop-2-enal##STR54##

Analogously to Example 10, 2.70 g of crude are obtained starting from2.13 g (7.1 mmol) of he compound of Example 22.

Yield: 100% of theory.

¹ H-NMR (CDCl₃):δ(ppm)=1.30 (d, 6H); 3.30 (m,1H); 4.15 (s, 3H); 5.95(dd, 1H); 7.0-7.25 (m, 5H); 9.3-9.4 (m, 2H).

Example 243,5-Di-[methyl-(E)-hydroxy-3-oxo-hept-6-enoat-7-yl]-4-(4-fluorophenyl)-6-isopropyl-1-methyl-pyrid-2-one ##STR55##

Analogously to Example 11, 1.04 g of crude product are obtained startingfrom 0.31 g (0.88 mmol) of the compound of Example 23.

Yield: 100% of theory.

¹ H-NMR (CDCl₃):δ(ppm)=1.1-1.4 (m, 6H); 2.3-2.7 (m, 4H); 3.2 (m, 1H);3,45 (m, 4H); 3.75 (m, 6H); 4.05 (s, 3H); 4.5 (m, 2H); 5.2 (m, 2H); 6.2(m, 2H); 6.8-7.2 (m, 4H).

Example 25 3.5-Di-[methyl-erythro-(E)-3,5-dihydroxy-hept-6-enoat-7-yl]-4-(4-fluorophenyl)-6-isopropyl-1-methyl-pyrid-2-one ##STR56##

Analogously to Example 12, 74 mg are obtained starting from 1.04 g (0.88mmol) of the compound of Example 24 after chromatography on silica gel(ethyl acetate/petroleum ether 1:1).

Yield: 14.3% of theory.

¹ H-NMR (CDCl₃):δ(ppm)=1.25 (m, 6H); 1.6 (m, 4H); 2.45 (m, 4H); 3.30(m,1H); 3.75 (2s, 6H); 4.05 (s, 3H); 4.15 (m, 2H); 4.30 (m, 2H); 5.25(dd, 2H); 6.2 (m, 2H); 6.95-7.15 (m, 4H).

Example 26 Ethyl3-benzyloxymethyl-4-(4-fluorophenyl)-6-isopropyl-1-methyl-pyrid-2-one-5-carboxylate##STR57##

Analogously to Example 7, the title compound is obtained starting from630 mg (1.9 mmol) of the compound from Example 6 and 720 mg of benzylbromide.

Yield: 92.2% of theory.

¹ H-NMR CDCl₃):δ(ppm)=0.9 (t, 3H); 1.3 (d, 6H); 3.05 (sept.,1H); 3.95(q, 2H); 4.03 (s, 3H); 4.2 (s, 2H); 4.4 (s, 2H); 7.0-7.4 (m, 9H);

Example 273-Benzyloxymethyl-40(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-1-methyl-pyrid-2-one##STR58##

Analogously to the procedure for Example 8, 520 mg of the title compoundare obtained starting from 700 mg (1.7 mmol) of the compound fromExample 26.

Yield: 77.4% of theory.

¹ H-NMR (CDCl₃)δ(ppm=1.32 (d, 6H); 3.4 (sept., 1H); 4.02 (s, 3H); 4.15(s, 2H); 4.3 (s, 2H); 4.38 (s, 2H); 7.0-7.4 (m, 9H).

Example 283-Benzyloxymethyl-4-(4-fluorophenyl)-6-isopropyl-1-methyl-pyrid-2one-5-carbaldehyde##STR59##

Analogously to Example 9, 400 mg of the title compound are obtainedstarting from 500 mg (1.3 mmol) of the compound of Example 27.

Yield: 78.3% of theory.

¹ H-NMR (CDCl₃):δ(ppm)=1.25 (d, 6H); 4.0 (sept., 1H); 4.08 (s, 3H); 4.15(s, 2H); 4.4 (s, 2H); 7.0-7.4 (m, 9H); 9.65 (s,1H).

Example 29 (E)-3-[3-Benzyloxymethyl-4-(4-fluorophenyl)-6-isopropyl-1-methyl-pyrid-2-on-5-yl]-prop-2-enal ##STR60##

Analogously to the procedure for Example 10, 400 mg of the titlecompound are obtained starting from mg (0.97 mmol) of the compound fromExample 28.

Yield: 78.3% of theory.

¹ H-NMR CDCl₃):δ(ppm)=1.28 (d, 6H); 3.32 (sept., 1H); 4.03 (s, 3H); 4.15(s, 2H); 4.38 (s, 2H); 5.88 (dd, 1H); 7.0-7.4 (m, 10H); 9.35 (d,1H).

Example 30 Methyl (E)-7-[3-benzyloxymethyl-4-(4-fluorophenyl)-6-isopropyl-1-methyl-pyrid-2-on-5-yl]-5-hydroxy-3-oxo-hept-6-enoate##STR61##

Analogously to Example 11, 70 mg of the title compound are obtainedstarting from 400 mg (0.76 mmol) of the compound of Example 29.

Yield: 20.9% of theory.

¹ H-NMR CDCl₃):δ(ppm)=1.25 (m, 6H); 2.45 (m, 2H); 3.22 (m,1H); 3.41 (s,2H); 3.72 (s, 3H); 4.0 (s, 3H); 4.15 (s, 2H); 4.4 (s, 2H); 4.48 (m, 1H);5.18 (dd,1H); 6.28 (d, 1H); 7.0-7.4 (m, 9H).

Example 31 Methyl erythro-(E)-7-[3-benzyloxymethyl-4-(4-fluorophenyl)-6-isopropyl-1-methyl-pyrid-2-on-5-yl]-3,5-dihydroxy-hept-6-enoate##STR62##

analogously to Example 12, 42 mg of the title compound are obtained asan oil starting from 70 mg (0.13 mmol) of the compound of Example 30.

Yield: 60.2% of theory.

¹ H-NMR (CDCl₃)δ(ppm)=1.1-1.5 (m, 8H); 2.4 (m, 2H); 3.25 (sept., 1H);3.72 (s, 3H); 4.02 (s, 3H); 4.08 (m, 1H); 4.15 (s, 2H); 4.3 (m, 1H);4.42 (s, 2H); 5.2 (dd, 1H); 6.26 (d, 1H); 7.0-7.4 (m, 9H).

Example 32 Ethyl 3-(tert.-butyldimethylsilyloxymethyl-4-(4-fluorophenyl)-6-isopropyl-1-methyl-pyrid-2-one-5-carboxylate ##STR63##

304 mg (2 mmol) of tert.-butyldimethylsilyl chloride, 262 mg (4 mmol) ofimidazole and 0.05 g of 4-dimethylaminopyridine are added at roomtemperature to a solution of 600 mg (1.8 mmol) of the compound fromExample 6 in 20 ml of dimethylformamide. The mixture is stirredovernight at room temperature, 200 ml of water are added and the mixtureis adjusted to pH 3 using 1 N hydrochloric acid. The mixture isextracted three times using 100 ml each of ether, and the combinedorganic phases are washed once with saturated sodium chloride solution,dried over magnesium sulphate and concentrated in vacuo. The residue ischromatographed on a column (150 g of silica gel, 70-230 mesh, φ 4 cm,using ethyl acetate/petroleum ether 1:9).

Yield: 700 mg (87% of theory.

¹ H-NMR CDCl₃):δ=0.0 (s, 6H); 0.85 (s, 9H); 0.95 (t, 3H); 1.3 (d, 6H);3.1 (m,1H); 3.95 (q, 2H); 4.0 (s, 2H); 4.35 (s, 3H); 7.05 (m, 2H); 7.35(m, 2H) ppm.

Example 33 Methylerythro-(E)-7-[3-tert.-butyldimethylsilyloxymethyl-4-(4-fluorophenyl)-6-isopropyl-1-methyl-pyrid-2-on-5-yl]-3,5-dihydroxy-hept-6-enoate##STR64##

Starting from Example 32, the title compound was prepared analogously tothe procedures of Examples 8-12.

¹ H-NMR CDCl₃):δ=0.0 (s, 6H); 0.9 (s, 9H); 1.25 (m, 6H); 1.5 (m, 2H);2.45 (m, 2H); 2.8 (m,1H); 3.3 (m, 1H); 3.6 (m,1H); 3.75 (s, 3H); 4.0 (s,3H); 4.1 (m,1H); 4.3 (m, 3H); 5.2 (dd,1H); 6.3 (d,1H); 7.0-7.3 (m, 4H)ppm.

Example 34 Methyl erythro-(E)-7-[4-(4-fluorophenyl-3-hydroxymethyl-6-isopropyl-1-methyl-pyrid-2-on-5yl]-3,5-dihydroxyl-hept-6-enoate ##STR65##

100 mg (0.18 mmol) of the compound from Example 33 are stirred overnightat room temperature in a solution of 1 ml of 1 N hydrochloric acid and 9ml of methanol. After concentrating, the mixture is taken up usingmethyl chloride, washed with saturated sodium hydrogen carbonatesolution, dried and filtered through silica gel (ethyl acetate/petroleumether 1:1).

Yield: 46 mg (57% of theory).

¹ H-NMR (CDCl₃):δ=1.2 (m, 6H); 1.4 (m, 2H); 2.4 (m, 2H); 3.4 (m, 1H);3.3 (m,1H); 3.55 (m,1H); 3.7 (s, 3H); 4.05 (s, 3H); 4.1 (m,1H); 4.35 (m,3H); 5.2 (dd,1H); 6.3 (d, 1H); 7.0-7.2 (m, 4H) ppm.

Example 35 Methyl 1-carbomethoxy -2-phenyl-propenoate ##STR66##

Analogously to Example 2, the title compound was obtained frombenzaldehyde and dimethyl malonate.

Yield: 97.3% of theory.

B.p.: 131° C./12 mm

¹ H-NMR CDCl₃):δ=3.75 (s, 6H); 7.4 (m, 5H); 7.8 (s,1H) ppm.

Example 36 Methylerythro-(E)-7-[6-isopropyl-3-methoxymethyl-1-methyl-4-phenyl-pyrid-2-on-5-yl]-3,5-dihydroxy-hept-6-enoate

Starting from Example 35, the title compound was obtained in analogy tothe procedures of Examples 3-12. ##STR67##

¹ H-NMR (CDCl₃):δ=1.2 (m, 6H); 1.4 (m, 2H); 2.4 (m, 2H); 2.6 (s,1H); 3.2(s, 3H); 3.25 (m,1H); 3.5 (m,1H); 3.7 (s, 3H); 4.0 (s, 3H); 4.1 (s, 2H);4.05 (m,1H); 4.25 (m, 1H); 5.2 (dd,1H); 6.3 (d,1H); 7.1-7.5 (m, 5H) ppm.

Example 37 Ethyl 3-amino-3-cyclopropyl-prop-2-enoate ##STR68##

Analogously to Example 1, the title compound was obtained from ethylcyclopropyl-carbonyl acetate.

B.p.: 63° C./0.3 mbar.

Yield: 24% of theory.

Example 38 Methyl erythro-(E)-7-[6-cyclopropyl-4-(4-fluorophenyl)-3-methoxymethyl-1-methyl-pyrid-2-on-5-yl]-3,5-dihydroxy-hept-6-enoate##STR69##

Starting from Example 37, the title compound was prepared in analogy tothe procedures of Examples 3-12.

¹ H-NMR (CDCl₃):δ=0.95 (m, 2H); 1.15 (m, 2H); 1.35 (m, 2H); 2.25 (m,1H);2.45 (m, 2H); 2.75 (s,1H); 3.2 (s, 3H); 3.5 (s,1H); 3.7 (s, 3H); 3.95(s, 3H); 4.05 (s, 2H); 4.1 (m,1H); 4.3 (m,1H); 5.5 (dd,1H); 6.3 (d,1H);7.0-7.2 (m, 4H) ppm.

By alkylating with ethyl iodide, benzyl bromide and 4-methoxybenzylchloride in analogy to the procedure for Example 5, the correspondingN-substituted derivatives were prepared which, again in analogy to theprocedures of Examples 6-12, were reacted to give the Products ofExamples 39, 40 and 41 hereinbelow.

Example 39 Methyl erythro-(E)-7-[1-ethyl-4-(4-fluorophenyl)-6-isopropyl-3-methoxymethyl-pyrid-2-on-5-yl]-3,5-dihydroxy-hept-6-enoate##STR70##

¹ H-NMR CDCl₃):δ=1.2 (m, 6H); 1.4 (m, 5H); 2.45 (m, 2H); 2.7 (s,1H); 3.2(s, 3H); 3.25 (m,1H); 3.5 (s,1H); 3.7 (s, 3H); 4.05 (m, 3H); 4.3 (m,1H);4.5 (q, 2H); 5.2 (dd, 1H); 6.25 (d,1H); 7.0-7.2 (m, 4H) ppm.

Example 40 Methyl erythro-(E)-7-[1-benzyl-4-(4-fluorophenyl)-6-isopropyl-3-methoxymethyl-pyrid-2-on-5-yl]-3,5-dihydroxy-hept-6-enoate##STR71##

¹ H-NMR (CDCl₃):δ=1.2 (m, 6H); 1.45 (m, 2H); 2.4 (m, 2H); 2.3 (s,1H);3.2 (s, 3H); 3.25 (m,1H); 3.5 (s,1H); 3.7 (s, 3H); 4.05 (m, 3H); 4.25(m, 1H); 5.2 (dd, 1H); 5.5 (s, 2H); 6.25 (d,1H); 7.0-7.5 (m, 9H) ppm.

Example 41 Methyl erythro-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-3-methoxymethyl-1-(4-methoxybenzyl)-pyrid-2-on-5-yl]-3,5-dihydroxy-hept-6-enoate ##STR72##

¹ H-NMR (CDCl₃):δ=1.2 (m, 6H); 1.45 (m, 2H); 2.4 (m, 2H); 2.7 (s, 1H);3.2 (s, 3H); 3.25 (m, 1H); 3.5 (s, 1H); 3.7 (s, 3H); 3.8 (s, 3H); 4.1(m, 1H); 4.3 (m, 1H); 5.2 (dd, 1H); 5.45 (d, 2H); 6.25 (d, 1H); 6.8-7.5(m, 8H) ppm.

Example 42 Ethyl3,4-dihydro-4(4-fluorophenyl)-6-isopropyl-(1H)-pyrid-2-one-5-carboxylate##STR73##

20.0 g (55 mmol) of the compound from Example 3 and 3.3 g of sodiumchloride were stirred for 2.5 h at 180° C. in 55 ml of dimethylsulphoxide and 2.5 ml of water and added to ice-water after cooling. Thesolid which precipitated was filtered off with suction andrecrystallized from ethanol.

M.p.: 119°-129° C.

Yield: 12.6 g (75% of theory).

Example 43 Methylerythro-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-1-methyl-pyrid-2-on-5-yl]-3,5-dihydroxy-hept-6-enoate ##STR74##

Starting from Example 42, the title compound was obtained analogously tothe procedures of Examples 4, 5 and 8-12.

¹ H-NMR (CDCl₃):δ=1.2 (d, 6H); 1.5 (m, 2H); 2.45 (m, 2H); 3.0 (s, 1H);3.3 (m,1H); 3.6 (s,1H); 3.7 (s, 3H); 3.95 (s, 3H); 4.1 (m,1H); 4.4(m,1H); 5.25 (dd,1H); 6.45 (m, 2H); 7.0-7.3 (m, 4H) ppm.

Use Example

The serum cholesterol-lowering action of the compounds according to theinvention on the blood cholesterol values of dogs was found in feedingexperiments of several weeks duration. For this purpose, the substanceto be investigated was given p.o. once daily in a capsule to healthybeagle dogs together with the feed over a period of time of severalweeks. During the entire experimental period, i.e. before, during andafter the administration period, the substance to be investigatedcholestyramine (4 g/100 g of feed) was additionally admixed to the feedas the gallic acid sequestrant.

Venous blood was taken from the dogs twice weekly and the serumcholesterol was determined enzymatically using a commercial test kit.The serum cholesterol values during the administration period werecompared with the serum cholesterol values before the administrationperiod (controls).

It is understood that the specification and examples are illustrativebut not limitative of the present invention and that other embodimentswithin the spirit and scope of the invention will suggest themselves tothose skilled in the art.

We claim:
 1. A ketone of the formula ##STR75## in which A representsaryl having 6 to 10 carbon atoms, which is optionally monosubstituted topentasubstituted by identical or different substituents from the groupconsisting of straight-chain or branched alkyl, alkylthio,alkylsulphonyl, alkoxy and alkoxycarbonyl each having up to 10 carbonatoms, which may in turn be substituted by hydroxyl, alkoxy having up to6 carbon atoms, phenyl or by a group of the formula --NR¹ R², or byaryl, aryloxy, arylthio or arylsulphonyl having 6 to 10 carbon atoms, orby halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, benzyloxy or a group of the formula --NR¹ R²,Brepresents straight-chain or branched alkyl having up to 12 carbonatoms, which is optionally substituted by halogen, cyano, azido,trifluoromethyl, trifluoromethoxy, trifluoromethylthio,trifluoromethylsulphonyl, alkoxy having up to 10 carbon atoms, aryl,aryloxy or arylthio having 6 to 10 carbon atoms where the aryl radicalsare optionally be monosubstituted to trisubstituted by identical ordifferent substituents from the group consisting of halogen, cyano,trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl,alkoxy, alkylthio and alkylsulphonyl each having up to 8 carbon atoms,or by a group of the formula --NR¹ R² or --COR³,in which R¹ and R² areidentical or different anddenote hydrogen, aryl or arylsulphonyl having6 to 10 carbon atoms, straight-chain or branched alkyl or alkylsulphonylhaving up to 8 carbon atoms, where said straight chain or branched alkylor alkylsulphonyl radicals are optionally substituted by aryl having 6to 10 carbon atoms, denote a group of the formula --COR³ in whichR³denotes straight chain or branched alkyl or alkoxy having up to 8 carbonatoms or phenyl, represents aryl having 6 to 10 carbon atoms ,which isoptionally monosubstituted to trisubstituted by identical or differentsubstituents form the group consisting of halogen, cyano, nitro,trifluoromethyl, straight-chain or branched alkyl, alkoxy andalkoxycarbonyl each having up to 8 carbon atoms or amino, representscycloalkyl having 3 to 8 carbon atoms, or represents straight-chain orbranched alky or alkenyl each having up to 12 carbon atoms andoptionally substituted by aryl having 6 to 12 carbon atoms or byhydroxyl, D and E are identical or different and represent a group ofthe formula --NR¹ R², --OR⁴ or --COR⁵,in which R⁴ denotes hydrogenordenotes straight-chain or branched alkyl having up to 10 carbon atoms,which is optionally substituted by hydroxyl, trialkylsilyl having up to10 carbon atoms in the entire alkyl moiety, halogen or aryl having 6 to10 carbon atoms, which may in turn be substituted by halogen, cyano,nitro, hydroxyl, straight-chain or branched alkyl, alkoxy oralkoxycarbonyl each having up to 8 carbon atoms or amino, denotestrialkylsilyl having up to 10 carbon atoms in the entire alkyl moiety,denotes cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10carbon atoms, optionally substituted by halogen, cyano, nitro or amino,or denotes a group of the formula --COR⁷, in whichR⁷ --denotesstraight-chain or branched alkyl having up to 8 carbon atoms aryl having6 to 10 carbon atoms or the --NR¹ R² group, R⁵ denotes hydrogen orstraight-chain or branched alkyl having up to 10 carbon atoms, which isoptionally substituted by hydroxyl, phenyl, halogen or cyano,denotesaryl having 6 to 10 carbon atoms optionally substituted by halogen,amino, hydroxyl, nitro or cyano, or denotes a group of the formula --NR¹R² or --OR⁴, G represents an oxygen or sulphus atom, and R¹⁰ representsalkyl having one to three carbon atoms.
 2. A ketone according to claim 1of the formula ##STR76##